LAUSR

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds 16g, 24b and 24e were measured by a STING competition binding assay. A more thorough study of the effect on the STING signaling pathway demonstrated that three compounds, 16g, 24b and 24e, significantly increased the protein levels and mRNA levels of IFN-β, CXCL10 and IL-6, and 24b as a representative compound effectively triggered the phosphorylation of STING, TBK1 and IRF3 both in human peripheral blood mononuclear cells (hPBMCs) and WT THP-1 cells. In addition, compound 24b demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. Furthermore, the pharmacokinetic profile of compound 24b was fully evaluated.